2-101008064-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001330348.2(TBC1D8):c.3225T>C(p.Phe1075=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00728 in 1,613,946 control chromosomes in the GnomAD database, including 96 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0073 (88 hom.)
• Consequence: TBC1D8 NM_001330348.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.244

Genes affected

TBC1D8 (HGNC:17791): (TBC1 domain family member 8) Predicted to enable GTPase activator activity. Predicted to be involved in activation of GTPase activity and intracellular protein transport. Predicted to be located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

RPL31 (HGNC:10334): (ribosomal protein L31) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 60S subunit. The protein belongs to the L31E family of ribosomal proteins. It is located in the cytoplasm. Higher levels of expression of this gene in familial adenomatous polyps compared to matched normal tissues have been observed. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-101008064-A-G is Benign according to our data. Variant chr2-101008064-A-G is described in ClinVar as [Benign]. Clinvar id is 774833.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.244 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBC1D8	NM_001330348.2	c.3225T>C	p.Phe1075=	synonymous_variant	20/20	ENST00000409318.2
TBC1D8	NM_001102426.3	c.3180T>C	p.Phe1060=	synonymous_variant	20/20
RPL31	NM_001098577.3	c.346+1993A>G		intron_variant
TBC1D8	NR_138475.2	n.3191T>C		non_coding_transcript_exon_variant	19/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D8	ENST00000409318.2	c.3225T>C	p.Phe1075=	synonymous_variant	20/20	5	NM_001330348.2	A1

Frequencies

GnomAD3 genomes AF: 0.00712 AC: 1084 AN: 152146 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.0545

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00809

Gnomad FIN AF: 0.0130

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00872

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00951 AC: 2369 AN: 249096 Hom.: 20 AF XY: 0.00974 AC XY: 1316 AN XY: 135160

Gnomad AFR exome AF: 0.000904

Gnomad AMR exome AF: 0.00307

Gnomad ASJ exome AF: 0.0549

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.0110

Gnomad FIN exome AF: 0.0133

Gnomad NFE exome AF: 0.00894

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.00730 AC: 10664 AN: 1461682 Hom.: 88 Cov.: 34 AF XY: 0.00764 AC XY: 5553 AN XY: 727126

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.00329

Gnomad4 ASJ exome AF: 0.0550

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0111

Gnomad4 FIN exome AF: 0.0129

Gnomad4 NFE exome AF: 0.00614

Gnomad4 OTH exome AF: 0.00875

GnomAD4 genome AF: 0.00711 AC: 1083 AN: 152264 Hom.: 8 Cov.: 32 AF XY: 0.00728 AC XY: 542 AN XY: 74450

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.00386

Gnomad4 ASJ AF: 0.0545

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00789

Gnomad4 FIN AF: 0.0130

Gnomad4 NFE AF: 0.00872

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.0116 Hom.: 7

Bravo AF: 0.00612

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00932

EpiControl AF: 0.00765

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	RPL31: BS1, BS2; TBC1D8: BP4, BP7, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	1.6
Dann	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs78831774; hg19: chr2-101624526; COSMIC: COSV99961423; COSMIC: COSV99961423;